The role of dopamine in health and disease has been investigated for decades. Dopamine receptor agonists or antagonists are used for the treatment diseases such as schizophrenia, depression, attention deficit disorder and Parkinson's disease. Recent work also indicates that the altered regulation of dopamine release induced by many drugs of abuse play a critical role in early processes linked to early aspects of addiction. Thus there is a considerable understanding of the physiological role of dopamine in the central nervous system. Recent work indicates that dopamine neurons that project of various areas in the CNS are remarkably heterogeneous. The heterogeneity is the result of variable intrinsic properties due to differential expression of ion channels and transmitter receptors. It is also clear that afferent inputs to dopamine neurons vary within the ventral midbrain. Thus experiments from dopamine neurons with identified projections is a necessary step in obtaining an understanding of the mechanisms that regulate dopamine release in functionally different areas of the CNS. This proposal uses recordings from identified dopamine neurons in brain slices from mouse to (1) define the inhibitory synaptic potential (IPSP) that results from the dendritic release. (2) Identify the distribution of D2 receptors on the somato-dendritic membrane and relate that distribution to identified synapses distinguished by the presence of PSD95. (3) Determine how D2-receptor function and distribution are altered following treatment of animals with cocaine. The results of this study will form a connection between cocaine-induced plasticity at AMPA and D2 receptor dependent synaptic events. The characterization of these early events following treatment with cocaine will add considerably to the decades long search for an understanding of the role of dopamine in health and disease.